Bruton's tyrosine kinase (Btk) is a member of the Tec family of non-receptor tyrosine kinases and plays a role in several hematopoietic cell signaling pathways, e.g., Toll like receptor (TLR) and cytokine receptor-mediated TNF-α production in macrophages, IgE receptor (FcεRI) signaling in Mast cells, inhibition of Fas/APO-1 apoptotic signaling in B lineage lymphoid cells, and collagen-stimulated platelet aggregation. See, e.g., Jeffries, et al. (2003) J. Biol. Chem. 278:26258-26264; Horwood et al. (2003) J. Exp. Med. 197:1603-1611; Iwaki et al. (2005) J. Biol. Chem. 280(48):40261-40270; Vassilev et al. (1999) J. Biol. Chem. 274(3):1646-1656, and Quek et al. (1998), Curr. Bio. 8(20):1137-1140. It is a particularly important in the signaling pathway initiated upon stimulation of the B cell receptor and during B cell development. Mutations in the Btk gene result in X-linked agammaglobulinemia, an immunodeficiency characterized by failure to produce mature B lymphocytes and associated with a failure of Ig heavy chain rearrangement. Rawlings and Witte (1994) Immun. Rev. 138:105-119. In the mouse, point mutation or deletion of Btk causes X-linked immunodeficiency (xid), with about 50% fewer conventional B2 B cells, absent B1 B cells, and reduced serum Ig levels. Khan et al (1995) Immunity 3:283-99; Rawlings et al (1993) Science 261:358-61. Btk is also expressed in specific cells of the myeloid lineage, and evidence suggests that it contributes to immune-complex mediated activation of the FcγR and FcεR signaling pathways in monocytes/macrophages, neutrophils, and mast cells. See, e.g., Jongstra-Bilen et al. (2008) J. Immunol. 181:288-298; Wang et al. (2007) Int. Immunopharmacol. 7:541-546; Hata et al. (1998) J Exp Med. 187:1235-1247.
Due to the role of Btk in inhibiting Fas/APO-1 apoptotic signals in the B cell lineage, inhibitors of Btk, also referred to as Btk inhibitors, have been evaluated as agents for treating hematopoietic malignancies (e.g., B cell lymphoma). Additionally, due to the role of Btk in the signaling pathways of other immune cells, Btk inhibitors have also been evaluated as agents for suppressing the immune system, e.g., in patients with autoimmune disorders or organ transplants. See, e.g., Honinberg et al. (2010) Proc. Natl. Acad. Sci. USA 107:13075-80; Chang et al. (2011) Arthr. Res. & Ther. 13:R115. Evidence for the role of Btk in autoimmune and/or inflammatory disease has been established in Btk-deficient mouse models. For example, in standard murine preclinical models of systemic lupus erythematosus (SLE), Btk deficiency has been shown to result in a marked amelioration of disease progression. Moreover, Btk deficient mice are also resistant to developing collagen-induced arthritis and are less susceptible to Staphylococcus-induced arthritis Inhibition of Btk activity is useful for the treatment of autoimmune and/or inflammatory diseases such as: SLE, rheumatoid arthritis, multiple vasculitides, idiopathic thrombocytopenic purpura (ITP), myasthenia gravis, and asthma. See, e.g., U.S. Pat. No. 7,393,848.
Btk inhibitors have also been shown useful in preventing or reducing the risk of thromboembolism. See, e.g., Uckun (2008) Int. Rev. Immunol. 27:43-69.